This application responds to RFA-DA-09-016, "Behavioral Pharmacology and Genetics: Translating and Targeting Individual Differences," and describes studies that will determine the genetic basis for individual differences in the effects of amphetamine (AMPH) on sensorimotor gating in clinically normal subjects. The operational measure of sensorimotor gating in these studies is prepulse inhibition of startle (PPI): the ability of a weak sensory event (prepulse) to inhibit the motor reflex response to a startling noise pulse. For 20 years, systematic studies in rodents have identified specific neural substrates regulating PPI. These limbic cortico- striatal-pallido-pontine substrates regulating PPI are implicated in the hedonic properties of drugs of abuse. PPI is a quantitative endophenotype, showing strong heritability in humans and rodents. The PI has identified heritable strain differences in the effects of the stimulant, d-amphetamine (AMPH), on PPI in rats, and individual differences in the effects of AMPH on PPI in human cohorts distinguished by physiological (level of baseline PPI) and psychological (levels of novelty seeking and sensation seeking) phenotypes. Both the strain differences and human phenotypes are also linked to neural and genetic determinants of forebrain dopaminergic function implicated as a powerful moderator of addiction liability. The goal of this application is to identify genes associated with individual differences in the effects of AMPH on PPI in humans. Candidates of strong inference for association studies will be: 1) genes associated with PPI AMPH sensitivity in rodents, and 2) genes associated with personality dimensions that characterize individuals who differ in PPI AMPH sensitivity. Based on our published findings, approximately 400 single nucleotide polymorphisms (SNPs) will be examined, allowing the interrogation of 20 different genes. Through the use of this quantitative, laboratory-based endophenotype, this application will identify genes that regulate individual differences in physiological, molecular and psychological moderators of addiction. PUBLIC HEALTH RELEVANCE: The goal of this application is to identify genes associated with individual differences in the effects of the psychostimulant, amphetamine, on sensorimotor gating in humans. Efforts will focus on genes associated with amphetamine effects on sensorimotor gating in rodents, and on genes associated with personality dimensions that characterize individuals who differ in amphetamine gating sensitivity. Through the use of this approach, this application will identify genes that regulate individual differences in physiological, molecular and psychological moderators of addiction.